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Compositions and methods for treating tissue ischemia

a technology of tissue ischemia and composition, applied in the direction of biocide, heterocyclic compound active ingredients, nitrile/isonitrile active ingredients, etc., can solve the problems of limited epcs capable of responding to angiogenic proteins, prohibitively expensive suggestions, and patients may not respond well to conventional therapeutic approaches, etc., to improve the presence of circulating epcs, promote neovascularization, and reduce the symptoms of or

Inactive Publication Date: 2006-08-31
STEWARD RES & SPECIALTY PROJECTS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013] We have found that particular cyclic polyamines can be used as effective CXCR4 antagonists. More specifically, we have learned that use of such antagonists desirably enhances presence of circulating EPCs in a subject mammal. Without wishing to be bound to theory, it is believed that the increase in EPCs can help to promote neovascularization, thereby reducing the symptoms of or in some instances eliminating potentially life-threatening consequences of tissue ischemia. Practice of the invention can be implemented before, during or after diagnosis of ishemia or a related condition with use after detection of tissue ischemia being generally preferred.
[0014] In one embodiment, the present methods can be used during or after AMI to enhance recruitment and incorporation of EPCs into sites where new vasculature is needed. Examples of such sites include those associated with damage to the myocardium and related tissue including supporting vasculature. In this embodiment, preferred practice of the invention reduces or eliminates many symptoms associated with AMI including, but not limited to, myocardial fibrosis and reduced left ventricle (LV) dilation. It is thus an object of the invention to provide effective treatments methods that include administering the CXCR4 antagonists to promote EPC mobilization and enhance neovascularization at or near sites of ischemia. In embodiments in which AMI is to be treated, such sites will often include peri-infarct myocardium.
[0016] Acceptable CXCR4 antagonists for use with the invention preferably induce EPC mobilization according to one or more assays as provided herein. Such antagonists also desirably assist neovascularization in the subject, particularly at or near sites impacted by tissue ischemia. By the term “induction” is meant enhancing EPC mobilization and preferably also facilitating formation of new blood vessels in ischemic tissue when compared to a suitable control (ie. without administration of the antagonist). By “EPC mobilization” is meant a significant increase in the number of peripheral blood EPCs as determined by assays disclosed herein.

Problems solved by technology

Thus, in certain patient populations, e.g., the elderly, EPCs capable of responding to angiogenic proteins may be limited.
Also, such patients may not respond well to conventional therapeutic approaches.
However, this suggestion is believed to be prohibitively expensive as it can require isolation and maintenance of patient cells.
Moreover, handling of patient cells can pose a significant health risk to both the patient and attending personnel in some circumstances.

Method used

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  • Compositions and methods for treating tissue ischemia
  • Compositions and methods for treating tissue ischemia
  • Compositions and methods for treating tissue ischemia

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cultured EPC Assay

[0117] Animals used in this study were handled in accordance with the guidelines of the Animal Care and Use Committee at St. Elizabeth's Medical Center of Boston. AMD3100 (125 μg in 100 μl of saline) was administered to eight-week old male FVB / N mice (Jackson Lab, Bar Harbor, Me.) by subcutaneous single injection. Control mice received 100 μl of saline by a similar procedure. Both groups of mice were sacrificed, and peripheral blood was harvested from subgroups of mice at 1, 3, 12 and 24 hours after injection. At each time point, blood was obtained from the heart immediately before sacrifice and separated by density gradient centrifugation with a Histopaque-1083 (Sigma). Light-density mononuclear cells were harvested and washed twice with Dulbecco's phosphate-buffered saline to which 5 mM EDTA had been added. Contaminated red blood cells were hemolyzed using ammonium chloride solution (Stem Cell Technologies).

[0118] Peripheral blood mononuclear cells (PBMNCS) wer...

example 2

Change of MNC and EPC Numbers By 24 Hours after a Single Injection of AMD-3100

[0120] Mice were injected as described in Example 1. As shown in FIG. 1, the numbers of both MNCs and EPCs rapidly increased after AMD-3100 injection, resulting in maximal MNCs and EPCs 1 hour after drug administration (613±89 cells / mm2 for AMD-3100 vs. 292±30 for control, P<0.01). The number of EPCs, identified by acLDL uptake and BS-1 lectin reactivity, increased at one hour after injection and returned to baseline within 24 hours after injection. These values returned to baseline within 24 hours (n=5 experiments).

example 3

Functional Study of AMD-3100 Injection after Myocardial Infarction

[0121] Eight-week old male FVB mice were anesthetized with sodium pentobarbital (50 mg / kg IP). The animals were intubated orally with a 22G IV catheter and artificially ventilated with a respirator (Harvard Apparatus). A left intercostal thoracotomy was performed and the ribs were retracted with 5-0 polypropylene sutures. After the pericardium was opened, the left anterior descending (LAD) branch of the left coronary artery was ligated proximal to the bifurcation between the LAD and the diagonal branch using 8-0 polypropylene sutures and visualized with a dissecting microscope. Positive end-expiratory pressure was applied to fully inflate the lungs, and the chest was closed with 7-0 polypropylene sutures. After the closure of chest wall, mice randomly received either a single subcutaneous injection of 125 μg AMD3100 (AMD group) or saline (control group). After physiological assessment at one, two and four weeks after...

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Abstract

The present invention generally provides methods for preventing or treating tissue ischemia using CXCR4 antagonists. In one embodiment, the methods include administering to a mammal a therapeutically effective amount of a particular bicylic polyamine to elevate peripheral blood EPCs. The invention has a wide spectrum of applications including reducing or eliminating tissue ishemica associated with a myocardial infarct (heart attack).

Description

RELATED APPLICATIONS [0001] The present application is a continuation application of International Application No. PCT / US2004 / 021299 (WO 2005 / 002522 A3) as filed on Jun. 30, 2004, which application claims priority to U.S. Provisional Application Ser. No. 60 / 484,052, filed Jun. 30, 2003. The disclosures of PCT / US2004 / 021299 and 60 / 484,052 applications are incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention relates to methods for preventing or treating tissue ischemia and related conditions. In one aspect, the invention provides methods for treating tissue ischemia by administrating to a mammal a therapeutically effective amount of at least one CXCR4 antagonist. The invention has a wide spectrum of useful applications including treating tissue ischemia associated with an acute myocardial infarction. BACKGROUND OF THE INVENTION [0003] There have been reports that endothelial progenitor cells (EPCs) can be isolated from peripheral blood, are augmented in...

Claims

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Application Information

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IPC IPC(8): A61K31/4439A61K31/33A61KA61K31/275A61K31/38A61K31/40A61K31/44
CPCA61K31/275A61K31/33A61K31/38A61K31/40A61K31/44A61K31/4439
Inventor LOSORDO, DOUGLAS W.BRIDGER, GARY J.ISNER, JEFFREY M.ISNER, LINDA
Owner STEWARD RES & SPECIALTY PROJECTS
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